MPN-038: PACIFICA: A Randomized, Controlled Phase 3 Study of Pacritinib Versus Physician’s Choice in Patients with Primary or Secondary Myelofibrosis and Severe Thrombocytopenia

Abstract

<h3>Background:</h3> Myelofibrosis is a serious, life-threatening myeloproliferative neoplasm caused by clonal proliferation of myeloid cells. Patients with myelofibrosis and severe thrombocytopenia (platelet counts <50x10⁹/L) are generally older, with more advanced disease and increased risk of bleeding, higher rates of anemia and complex/unfavorable cytogenetics, and shortened overall survival compared to patients with higher platelet counts. Currently, approved JAK2 inhibitors have not been studied in patients with severe thrombocytopenia. For such patients, NCCN guidelines suggest enrollment in clinical trials due to limited therapeutic options. Pacritinib is an oral JAK2/IRAK1 inhibitor with demonstrated clinical activity in myelofibrosis in two phase 3 studies and a phase 2 dose-finding study; all included patients with have severe thrombocytopenia. The PACIFICA trial (NCT03165734) is designed to evaluate efficacy and safety of pacritinib 200 mg twice daily <i>versus</i> physician's choice (P/C) therapy in myelofibrosis patients with severe thrombocytopenia. <h3>Study Design:</h3> PACIFICA is a multi-national, multi-center, randomized, controlled phase 3 trial of pacritinib versuss P/C in adults with primary or secondary myelofibrosis with DIPSS intermediate- or high-risk disease, ECOG PS 0-2, platelet counts <50 x 10⁹/L, limited or no prior JAK2 inhibitor treatment, and are not candidates for stem cell transplant. Additional exclusion criteria include recent grade ≥2 cardiac or hemorrhagic events, LVEF <50%, QTc >450 msec, or use of medications that increase risk of hemorrhage or QT prolongation. Approximately 348 patients will be randomized 2:1 to continuous pacritinib 200 mg twice daily or P/C (low-dose ruxolitinib, danazol, corticosteroids, or hydroxyurea). The primary objective is efficacy as assessed by proportion of patients achieving a ≥35% spleen volume reduction (SVR) from baseline to week 24. Secondary objectives include proportion of patients achieving a ≥50% reduction in total symptom score at week 24, Patient Global Impression of Change responses at week 24, overall survival, and safety. Tertiary endpoints include leukemia-free survival, alternative SVR analyses, hematologic improvement (transfusion independence and improvement in hemoglobin and platelet levels), fatigue improvement, and changes in biomarkers and gene expression. The primary analysis will be based on ~168 patients; secondary analyses will be based on the full sample size. PACIFICA is currently enrolling, with ~130 sites worldwide.